Efficient Simultaneous Tumor Targeting Delivery of All-Trans Retinoid Acid and Paclitaxel Based on Hyaluronic Acid-Based Multifunctional Nanocarrier

Abstract

An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). The HRA conjugate was synthesized by an imine reaction between HA-COOH and ATRA-NH2. PTX-loaded HRA nanoparticles possessed a high loading capacity, nanoscale particle sizes, and good biocompatible characteristics. Cell viability assays indicated that PTX-loaded HRA nanoparticles exhibited concentration- and time-dependent cytotoxicity. Moreover, they displayed obvious superiority in inducing the apoptosis of tumor cells. Cellular uptake analysis suggested that HRA nanoparticles could be efficiently taken up by cells via endocytic pathway and transport into the nucleus, contributing to HA receptor-mediated endocytosis and ATRA-induced nuclear translocation, respectively. Moreover, in vivo imaging analysis indicated that the accumulation of DiR-loaded HRA nanoparticles in tumor was increased obviously after intravenous administration as compared to free DiR solution, which confirmed that the HRA nanoparticles could assist the drugs targeting to the tumor. Furthermore, PTX-loaded HRA nanoparticles exhibited greater tumor growth inhibition effect in vivo with reducing the toxicity. Therefore, HRA nanoparticles can be considered as a promising targeted codelivery system for combination cancer chemotherapy.

Nanoparticle delivery and combination therapy of gambogic acid and all-trans retinoic acid

“…In addition, HRA conjugate also did not cause hemolysis with the range of equivalent doses. 21 As shown in Figure 3B, the histopathologic examination of the rabbit ear-border vein after a 3-day administration of GA-HRA showed no angiectasia or thrombus formation in the vein lumen, similarly to the control group and the HRA conjugate group. In addition, no erythema or edema response was noticed in the rabbit ears after multidose administration, unlike GA solution where serious intravenous irritation was observed.…”

“…21 In brief, aminoethyl ATRA was first synthesized and then reacted with the carboxylic acids of HA in the presence of EDC and N-hydroxysuccinimide. The products were characterized by proton nuclear magnetic resonance (Avace AV-500; Bruker, Ettlingen, Germany).…”

“…20 We have successfully synthesized an amphiphilic HA derivative (HRA conjugate) with all-trans retinoic acid (ATRA) as a hydrophobic group as reported in our previous study. 21 In this study, HRA conjugate was used to encapsulate GA by self-assembling into nanoparticles in order to improve the aqueous solubility and in vitro and in vivo properties of GA. Interestingly, ATRA can inhibit the cancer cell proliferation and induce cell differentiation of malignant cells. 22 The combination of ATRA and other cytotoxic drugs such as PTX displayed greater and synergistic antitumor effect.…”

Enhanced antitumor and anti-metastasis efficiency via combined treatment with CXCR4 antagonist and liposomal doxorubicin

“…Fig. 3B and C showed that free DOX exhibited stronger inhibition effect compared to other two groups as the IC 50 value is 3.77 μM, which may be due to the reason that free drugs could be quickly transported into cells by passive diffusion with high concentration gradient [26]. The inhibition rate of DOX-Lip and DOX-Lip + Peptide S were both lower than free DOX, but there is no significant difference between the two groups (6.03 μM and 5.81 μM for DOX-Lip and DOX-Lip + Peptide S respectively) because Peptide S showed no inhibitory effect on cell viability even at concentration up to 100 μM (Fig.…”

Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy

“…In one example, HA was conjugated with all- trans retinoid acid, a hydrophobic anticancer drug, to form micelles around paclitaxel. This HA nanosystem was found to have low nonspecific toxicity and high antitumor efficacy in the B16 melanoma model (Yao, Zhang, Zhou, Liu, & Zhang, 2013). Another example of synergistic therapy via HA nanoparticles involves adsorption of a photodynamic therapy agent, hematoporphyrin monomethyl ether, onto HA-derivatized carbon nanotubes.…”